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1.
Brain Res ; 1747: 147067, 2020 11 15.
Article in English | MEDLINE | ID: mdl-32827548

ABSTRACT

Research focusing on the gut-brain axis is growing, but the interplay of ethanol (alcohol molecule), the gut microbiome, the brain and behavior is poorly understood. In the current study, we remodeled the gut microbiota by providing adult male C57BL/6J mice with a non-absorbable antibiotic cocktail (ABX) in the drinking water and tested ethanol consumption behavior in a binge-like "Drinking in the Dark" model. Notably, 2 weeks of ABX pre-treatment significantly increased ethanol consumption during the 6 weeks of ethanol exposure in the DID paradigm. ABX treatment also appeared to prevent anxiety-like behavior during ethanol withdrawal period. ABX-treated mice expressed reduced bacterial diversity and modified microbiota compositions within cecal samples. There were drastically reduced levels of commensal Firmicutes and increases in the Bacteroidetes and Verrucomicrobia populations. Importantly, the relative abundance of Firmicutes inversely correlated to ethanol intake levels regardless of antibiotic treatment, whereas Bacteroidetes and Verrucomicrobia populations negatively correlated to ethanol intake levels. This is the first report demonstrating that ABX-induced disruption of the gut commensal microbiota leads to increased ethanol consumption in mice. This work reveals an important relationship between the gut microbiota and ethanol consumption behavior and supports the use of microbial-targeted approaches to study gut-brain interactions during alcohol use disorder.


Subject(s)
Alcohol Drinking , Anti-Bacterial Agents/pharmacology , Metagenome/drug effects , Microbiota/drug effects , Animals , Ethanol/blood , Male , Mice
2.
Clin Pharmacol Transl Med ; 3(1): 134-142, 2019.
Article in English | MEDLINE | ID: mdl-31321385

ABSTRACT

BACKGROUND/AIMS: The prevalent comorbidity between neuropsychiatric and gastrointestinal (GI) disorders is believed to be significantly influenced by gut microbiota (GM). GM may also play a substantial role in comorbidity between substance abuse (e.g. Alcohol Use Disorder, AUD) and depression. The anti-parasitic drug Moxidectin (MOX) has been reported to reduce alcohol intake in male and female mice. This effect is purported to be centrally mediated with a significant contribution linked to purinergic, P2X4 purinergic receptors. However, MOX's effects on GM in animal models of depression is not known. METHODS: Adult male Wistar Kyoto (WKY) rats (5/group) were injected intraperitoneally (i.p.) once daily for 7 days with MOX (2.5mg/kg), or saline as control group. On day 8, approximately 20 h after the last MOX injection, animals were sacrificed, intestinal stools were collected and stored at -80°C DNA was extracted from the samples for 16S rRNA gene-based GM analysis using 16S Metagenomics application. RESULTS: At taxa and species level, MOX affected a number of bacteria including a 30-fold increase in Bifidobacterium cholerium, a bacterium with a strong ability to degrade carbohydrates that resist digestion in the small intestine. There was a minimum of 2-fold increase in: five probiotic species of Lactobacillus, butyrate-forming Rosburia Facies and Butyrivibro proteovlasticus. In contrast, MOX depleted 11 species, including 2 species of Ruminoccus, which are positively associated with severity of irritable bowel syndrome, and 4 species of Provettela, which are closely associated with depressive-like behavior. CONCLUSION: Thus, MOX enhanced probiotic species, and suppressed the opportunistic pathogens. Since overall effect of MOX appears to be promoting GM associated with mood enhancement (e.g. Bifidobacterium and Lactobacillus) and suppressing GM associated with inflammation (e.g. Ruminoccus), potential antidepressant and anti-inflammatory effects of MOX in suitable animal models should be investigated.

3.
J Neuroimmune Pharmacol ; 14(2): 263-277, 2019 06.
Article in English | MEDLINE | ID: mdl-30353422

ABSTRACT

Chronic low-grade neuroinflammation is increasingly implicated in organ damage caused by alcohol abuse. Purinergic P2X7 receptors (P2X7Rs) play an important role in the generation of inflammatory responses during a number of CNS pathologies as evidenced from studies using pharmacological inhibition approach. P2X7Rs antagonism has not been tested during chronic alcohol abuse. In the present study, we tested the potential of P2X7R antagonist A804598 to reduce/abolish alcohol-induced neuroinflammation using chronic intragastric ethanol infusion and high-fat diet (Hybrid) in C57BL/6J mice. We have previously demonstrated an increase in neuroinflammatory response in 8 weeks of Hybrid paradigm. In the present study, we found neuroinflammatory response to 4 weeks of Hybrid exposure. A804598 treatment reversed the changes in microglia and astrocytes, reduced/abolished increases in mRNA levels of number of inflammatory markers, including IL-1ß, iNOS, CXCR2, and components of inflammatory signaling pathways, such as TLR2, CASP1, NF-kB1 and CREB1, as well in the protein levels of pro-IL-1ß and Nf-kB1. The P2X7R antagonist did not affect the increase in mRNA levels of fraktalkine (CX3CL1) and its receptor CX3CR1, an interaction that plays a neuroprotective role in neuron-glia communication. P2X7R antagonism also resulted in reduction of the inflammatory markers but did not alter steatosis in the liver. Taken together, these findings demonstrate how P2X7R antagonism suppresses inflammatory response in brain and liver but does not alter the neuroprotective response caused by Hybrid exposure. Overall, these findings support an important role of P2X7Rs in inflammation in brain and liver caused by combined chronic alcohol and high-fat diet. Graphical Abstract ᅟ.


Subject(s)
Chemical and Drug Induced Liver Injury/psychology , Encephalitis/chemically induced , Encephalitis/prevention & control , Guanidines/pharmacology , Purinergic P2X Receptor Antagonists/pharmacology , Quinolines/pharmacology , Receptors, Purinergic P2X7/drug effects , Animals , Astrocytes/drug effects , Astrocytes/pathology , Central Nervous System Depressants/blood , Chemical and Drug Induced Liver Injury/pathology , Cytokines/metabolism , Diet, High-Fat , Encephalitis/pathology , Ethanol/blood , Gene Expression Regulation/drug effects , Hippocampus/pathology , Male , Mice , Mice, Inbred C57BL , Microglia/drug effects , Microglia/pathology
4.
J Steroid Biochem Mol Biol ; 144 Pt A: 22-7, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24388948

ABSTRACT

Provided here is a collective review of research on the extrarenal CYP27B1-hydroxylase that shapes our current and expanding vision of the role this enzyme plays in the intracrinology and paracrinology, as opposed to the traditional endocrinology, of vitamin D to regulate the innate and adaptive immune responses, particularly in human granuloma-forming diseases like tuberculosis. Special emphasis is placed on soluble factors (i.e., cytokines) in the local microenvironment of these human diseases that coordinate amplification and feedback inhibition of the macrophage CYP27B1-hydroxylase. Principal among these factors are Type I and Type II interferons (IFNs); the Type II IFN, IFN-γ, stimulates the production of 1,25-dihydroxyvitamin D (1,25(OH)2D) from 25-hydroxyvitamin D (25OHD) by the granuloma-forming disease-activated macrophage, while the Type I IFNs, IFN-α and IFN-ß, block the hydroxylation reaction. The Type I IFN response is associated with more aggressive disease, while the Type II IFN response, the one that promotes 1,25(OH)2D production by the macrophage, is associated with more confined disease. Tilting the balance in the human immune response toward a confined disease phenotype is enabled by the presence of sufficient extracellular 25OHD to modulate IFN-γ-promoted and substrate 25OH-driven intracellular synthesis of 1,25(OH)2D. This article is part of a Special Issue entitled 'Vitamin D Workshop'.


Subject(s)
25-Hydroxyvitamin D3 1-alpha-Hydroxylase/genetics , Macrophages/enzymology , Receptors, Calcitriol/metabolism , Vitamin D/analogs & derivatives , 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/metabolism , Animals , Gene Expression Regulation , Humans , Transcription, Genetic , Vitamin D/metabolism
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